Anatomical Variants of the Renal Veins and Their Relationship with Morphofunctional Alterations of the Kidney: A Systematic Review and Meta-Analysis of Prevalence

Background: Variations in renal veins are quite common, and most people do not experience issues due to them. However, these variations are important for healthcare professionals, especially in surgical procedures and imaging studies, as precise knowledge of vascular anatomy is essential to avoid complications during medical interventions. The purpose of this study was to expose the frequency of anatomical variations in the renal vein (RV) and detail their relationship with the retroperitoneal and renal regions. Methods: A systematic search was conducted in the Medline, Scopus, Web of Science, Google Scholar, CINAHL, and LILACS databases from their inception until January 2024. Two authors independently carried out the search, study selection, and data extraction and assessed methodological quality using a quality assurance tool for anatomical studies (AQUA). Ultimately, consolidated prevalence was estimated using a random effects model. Results: In total, 91 studies meeting the eligibility criteria were identified. This study included 91 investigations with a total of 46,664 subjects; the meta-analysis encompassed 64 studies. The overall prevalence of multiple renal veins was 5%, with a confidence interval (CI) of 4% to 5%. The prevalence of the renal vein trajectory was 5%, with a CI of 4% to 5%. The prevalence of renal vein branching was 3%, with a CI of 0% to 6%. Lastly, the prevalence of unusual renal vein origin was 2%, with a CI of 1% to 4%. Conclusions: The analysis of these variants is crucial for both surgical clinical management and the treatment of patients with renal transplant and hemodialysis.


Introduction
In their usual route, the renal veins (RVs) form in the renal hilum.Along this route, the right renal vein (RRV) receives tributaries, while the left renal vein (LRV) receives the left adrenal vein and the left gonadal vein, ending its journey in the inferior vena cava (IVC) at the level of the L1 vertebra.However, they do not present this way in all individuals, since variants may arise in embryonic development [1,2].Particularly, when studying RV anatomy, any greater complexity in the RV, due to its relationship with the abdominal aorta (AA) and the superior mesenteric artery (SMA), has its beginning in the embryonic development of these vessels.If anomalies occur in the embryogenesis of this vein, it can surround the AA or the discourse posterior to it.These phenomena are known as the circumaortic renal vein or retroaortic renal vein, respectively.Another important RV variation involves supernumerary veins, also known as multiple RV; instead of one venous trunk, up to four can be found.These variations are more frequently associated with the RRV.Finally, another variation occurs in the accessory vessels that contribute to the RV, including the posterior tributary vein, which connects the posterior course with the renal pelvis [3][4][5][6].
These RV variations have been widely described in meta-analyses of case studies and cadaveric dissections, although the statistics and analysis of their incidences are hardly discussed in the literature.Several studies highlight the importance of these variations in the clinical context.Although they generally do not present symptoms, associations have been described, such as RV hypertension syndrome, in which renal venous hypertension causes venous flow to be directed retrogradely towards the renal parenchyma, generating ruptures of veins in the collecting system.Another syndrome studied in association with these variations is posterior nutcracker syndrome, which presents with macroscopic hematuria and/or associated proteinuria due to compression of the RV.These syndromes have been associated with both variations of LRV described above.Understanding these variations and their incidences can prevent unfavorable results or poor intraoperative practices.The importance of the different renal patterns in renal transplantation and radical nephrectomy cannot be underestimated.Knowledge of the architecture of the renal vessels and a study beforehand to clarify the presence of these variations can be essential to the success of these procedures, especially with the great radiological advances in recent years [7][8][9].
The objective of this review was to know the characteristics and prevalence of the anatomical variants of RV and their relationship with renal pathologies and the importance of knowledge of this anatomical variant in surgeries.

Methodology 2.1. Protocol and Registration
To carry out this meta-analysis, we were guided by the Prisma statement.The registration number in the Systematic Reviews Registry (PROSPERO) is CRD42022224066.

Electronic Search
In order to have the best studies that fit our research question, we searched the following databases during the months of October and November: MEDLINE (via PubMed), Google Scholar, Web of Science (WOS), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American and the Caribbean Literature in Health Sciences (LILACS), and Scopus from its inception until November 2023.Our search strategy included a combination of the following terms: "renal vein" (Mesh), "renal failure" (not Mesh), "renal vein variations" (not Mesh), "vascularization kidney" (not Mesh), "anatomical variation" (not Mesh), "kidney surgery" (Mesh), and "kidney transplant" (Mesh), using the Boolean connectors AND, OR, and NOT.

Eligibility Criteria
As eligibility criteria, the studies that were included considered the presence of RV variants and their association with some clinical conditions.They were considered eligible for inclusion if the following criteria were met: (1) sample: dissections or images with the presence of the RV variation; (2) results: prevalence of subjects who presented RV variants and their correlation with pathologies of the retroperitoneal region; (3) studies: this systematic review included research articles, retrospective and prospective observational types, published in English in peer-reviewed journals, and indexed in the reviewed databases.
As exclusion criteria we used the following to eliminate from our selection: (1) sample: studies carried out in animals; (2) studies that analyzed variants of the venous system outside the renal region or its drainage area or tract; (3) letters to the editor or comments.

Study Selection
In order to make a thorough selection of the studies, we three authors analyzed the material independently.In the first instance, two authors (KV and MT) examined the titles and abstracts of the references recovered from the database searches.For the selected studies, the full text of the references that any of the authors considered potentially relevant was obtained.A third reviewer (PN) was involved if a consensus could not be reached.For this purpose, we also performed the agreement test between authors, the kappa test, to analyze reliability and the risk of bias between observers, which in this case gave 0.70, which is interpreted as a good agreement.

Data Collection Process
Two authors (MO and KV) independently extracted data on the outcomes of each study.The following data were extracted from the included studies: (a) authors and year of publication, (b) country, (c) type of study and number of participants, (d) sample characteristics and prevalence, (e) reported statistical values, (f) region geography of the study, (g) sex of the sample, and (h) laterality of the presence of the variant (right, left, and bilateral).

Assessment of the Methodological Quality of the Included Studies
To evaluate the bias of the included studies, we used the verification table for anatomical studies (AQUA) proposed by the International Working Group on Evidence-Based Anatomy (IEBA) [10].Two reviewers (JJV and JM) independently analyzed the 5 domains proposed by the AQUA tool, then reached a consensus and constructed the table and the bias graph.

Publication Bias
Through JAMOVI, we made funnel plots.For publication bias, we have the funnel plot graph, where theoretically the data that most affect this criterion are the statistical significance of the primary article and its sample; this graph crosses the sample measurement against the exposure association or confidence interval transformed into standard error against the sample size.

Statistical Methods
For the statistical analysis, we used the JAMOVI technological tool Version 4.0 2022 (R Core Team, 2021) [11].Where we included the data in a binary way and continuously to obtain the proportion of the data which we expressed in prevalence, the statistical model used was the DerSimonian-Laird with a Freeman-Tukey double-arcsine transformation to combine the summarized data.Additionally, a random effects model was used because the VD prevalence data were very heterogeneous.The degree of heterogeneity among the included studies was assessed using the chi 2 test and the heterogeneity statistic (I 2 ).Finally, with the JAMOVI tool, we analyzed a funnel plot graph where the magnitude of the measured effect is represented, which is graphed in a funnel plot [10].

Included Articles
The researchers identified a total of 1456 articles in various databases that met the established criteria and search terms.Titles and/or abstracts of the articles in the con-sulted databases were filtered, primarily using duplicate elimination as the initial criterion.Subsequently, 180 full-text articles were analyzed to determine their eligibility in this metaanalysis and systematic review.A total of 148 studies were excluded due to discrepancies in primary and secondary outcomes concerning this review and not meeting the criteria for corresponding data extraction.As a result, 90 articles (n = 46,664) were included for analysis, encompassing patients, images, and cadavers (Figure 1).

Included Articles
The researchers identified a total of 1456 articles in various databases that met the established criteria and search terms.Titles and/or abstracts of the articles in the consulted databases were filtered, primarily using duplicate elimination as the initial criterion.Subsequently, 180 full-text articles were analyzed to determine their eligibility in this metaanalysis and systematic review.A total of 148 studies were excluded due to discrepancies in primary and secondary outcomes concerning this review and not meeting the criteria for corresponding data extraction.As a result, 90 articles (n = 46,664) were included for analysis, encompassing patients, images, and cadavers (Figure 1).

Characteristics of the Studies and the Study Population
The samples analyzed in the reviewed studies came from all continents except Oceania.In Europe, 36 studies were conducted, representing 40% of the total.The cumulative number of patients in these studies was 33,790, consolidating 72.41% of the reviewed samples.A total of 18 studies (20%) were carried out in Asia, with a total of 3368 patients, representing 7.22% of the analyzed samples.In North America, 21 studies were conducted (23.3%), with a cumulative number of 7048 patients, representing 15.1% of the samples.South America had nine studies (10%) with a total of 969 patients, accounting for 2.07% of the samples in our analysis (Table 1 and Figure 2).Finally, in Africa, six studies were conducted (6.6%), with a cumulative total of 1489 patients, representing 3.19% of the sample size in our analysis.

Characteristics of the Studies and the Study Population
The samples analyzed in the reviewed studies came from all continents except Oceania.In Europe, 36 studies were conducted, representing 40% of the total.The cumulative number of patients in these studies was 33,790, consolidating 72.41% of the reviewed samples.A total of 18 studies (20%) were carried out in Asia, with a total of 3368 patients, representing 7.22% of the analyzed samples.In North America, 21 studies were conducted (23.3%), with a cumulative number of 7048 patients, representing 15.1% of the samples.South America had nine studies (10%) with a total of 969 patients, accounting for 2.07% of the samples in our analysis (Table 1 and Figure 2).Finally, in Africa, six studies were conducted (6.6%), with a cumulative total of 1489 patients, representing 3.19% of the sample size in our analysis.
Regarding the focus of the studies, 42 analyzed the renal vein bilaterally, while 4 focused only on the right side and 44 only on the left side.In addition, of the patients included in the reviewed studies, 31.91% were male, 25.63% were female, and 41.19% chose not to specify their gender (Table 1).

Description of Variants
Among the RV variants found in the literature that we analyzed in this prevalence study, variations were found at the level of origin of the RV and the trajectory of the RV; additionally, some cases included multiple RV and variations in the ramifications of the RV.For the variants in the origin of the RV, a variant of origin of LRV was considered any situation in which the RV, both unilaterally and bilaterally, arose from a level lower than L2-L3 from the IVC; the RV arose from a different site to the IVC; the drainage occurred at the level of the lateral aspect of the IVC; or a late venous confluence was present where both the origin of the RV and its path towards the renal hilum were affected.For the RV course variants, the normal course of the RV was considered in which the RV crossed the anterior part of the AA to drain into the IVC.The variants observed in the literature with the highest prevalence were the retroaortic and circumaortic paths of RV (Figures 3 and 4).A retroaortic RV path is any path in which the RV crosses the posterior part of the AA, finally draining into the IVC; a circumaortic course is one in which the RV forms a circle around the AA and drains into the IVC.For the multiple RV variant, all RVs with a single vascular trunk were considered normal.The ones with double, triple, and quadruple trunk of the RV were considered multiple RV variants, either unilaterally or bilaterally.Finally, all cases in which the RV had one or more accessory branches and the latter ending up draining into the IVC were considered the RV branching variant (Figure 5).
finally draining into the IVC; a circumaortic course is one in which the RV forms a circle around the AA and drains into the IVC.For the multiple RV variant, all RVs with a single vascular trunk were considered normal.The ones with double, triple, and quadruple trunk of the RV were considered multiple RV variants, either unilaterally or bilaterally.Finally, all cases in which the RV had one or more accessory branches and the latter ending up draining into the IVC were considered the RV branching variant (Figure 5).

Risk of Bias of Included Articles
A total of 79 articles were evaluated with the AQUA checklist to analyze the risk of bias in five domains (Figure 10).For the first domain, which covers the description of the objectives and characteristics of the study, all studies presented a low risk of bias.The second domain is the correct reporting of the study design.A total of 76 studies presented a low risk of bias in this domain, and 3 presented a high risk since they did not clearly report the design of their studies [18,75,94].For the third domain, which analyzes the study's methodological characteristics, 77 studies presented a low risk of bias, while 2 presented a high risk since their methodology was unclear [32,70].The fourth domain is the correct description of anatomy.A total of 78 studies presented a low risk of bias in this domain, while only 1 study presented a higher risk since it did not include an anatomical description of the variant but instead merely named it [88].In the final domain, which involves reporting results, 72 studies presented a low risk of bias, 2 presented their results

Risk of Bias of Included Articles
A total of 79 articles were evaluated with the AQUA checklist to analyze the risk of bias in five domains (Figure 10).For the first domain, which covers the description of the objectives and characteristics of the study, all studies presented a low risk of bias.The second domain is the correct reporting of the study design.A total of 76 studies presented a low risk of bias in this domain, and 3 presented a high risk since they did not clearly report the design of their studies [18,75,94].For the third domain, which analyzes the study's methodological characteristics, 77 studies presented a low risk of bias, while 2 presented a high risk since their methodology was unclear [32,70].The fourth domain is the correct description of anatomy.A total of 78 studies presented a low risk of bias in this domain, while only 1 study presented a higher risk since it did not include an anatomical description of the variant but instead merely named it [88].In the final domain, which involves reporting results, 72 studies presented a low risk of bias, 2 presented their results

Risk of Bias of Included Articles
A total of 79 articles were evaluated with the AQUA checklist to analyze the risk of bias in five domains (Figure 10).For the first domain, which covers the description of the objectives and characteristics of the study, all studies presented a low risk of bias.The second domain is the correct reporting of the study design.A total of 76 studies presented a low risk of bias in this domain, and 3 presented a high risk since they did not clearly report the design of their studies [18,75,94].For the third domain, which analyzes the study's methodological characteristics, 77 studies presented a low risk of bias, while 2 presented a high risk since their methodology was unclear [32,70].The fourth domain is the correct description of anatomy.A total of 78 studies presented a low risk of bias in this domain, while only 1 study presented a higher risk since it did not include an anatomical description of the variant but instead merely named it [88].In the final domain, which involves reporting results, 72 studies presented a low risk of bias, 2 presented their results unclearly, and 5 studies presented a high risk of bias since their results were presented diffusely in tables or in discussion sections [18,57,75,88,94] (Figure 14).
unclearly, and 5 studies presented a high risk of bias since their results were presented diffusely in tables or in discussion sections [18,57,75,88,94] (Figure 14).For the analysis of studies with case report methodology, the JBI tool was used to assess the risk of bias.A total of 12 studies were analyzed within the eight domains of this bias tool [13,14,16,19,35,40,48,52,55,71,93,99].The majority presented a low risk of bias in domains 1 to 6.However, in domain 7, which focuses on adverse events (harms) or unanticipated events, seven studies presented a high risk of bias [13,14,16,19,52,71,99].Domain 8 analyzes whether the case report provides takeaway lessons.Seven studies presented a high risk of bias since they did not comply with what was proposed in this domain (Tables 3 and 4) [13,14,16,40,52,55,71].  [16] Low Senecail et al., 2003 [71] Low Silva, 2021 [14] Low For the analysis of studies with case report methodology, the JBI tool was used to assess the risk of bias.A total of 12 studies were analyzed within the eight domains of this bias tool [13,14,16,19,35,40,48,52,55,71,93,99].The majority presented a low risk of bias in domains 1 to 6.However, in domain 7, which focuses on adverse events (harms) or unanticipated events, seven studies presented a high risk of bias [13,14,16,19,52,71,99].Domain 8 analyzes whether the case report provides takeaway lessons.Seven studies presented a high risk of bias since they did not comply with what was proposed in this domain (Tables 3 and 4) [13,14,16,40,52,55,71].

Clinical Considerations
Among the 90 studies analyzed in this review, 59 demonstrated some clinical correlation to the various anatomical variations of RV.For the most part, these variations are clinically silent [29,33,39,47,67,77,83]; however, when they produce symptoms, we can observe syndromes such as the "nutcracker syndrome" [2,22,24,29,41,65,100], which corresponds to a compression of the LRV in its retroaortic variation caused by the SMA (superior mesenteric artery) and the AA (abdominal aorta).This syndrome is rare and classically presents with proteinuria and hematuria; therefore, it is diagnosed through laboratory tests, such as urinalysis [25,29,31,34,39,42,58,65,83].It can also have significant complications, such as dilation of the gonadal vein, generating varicocele in men [2,22,23,25,34,42,61,65], and pelvic congestion syndrome in women [29,39,58,83].Varicocele is the dilation of the veins within the scrotum.It is usually asymptomatic but can cause a decrease in sperm production and quality, which may eventually lead to infertility.On the other hand, pelvic congestion syndrome in women is the accumulation of venous blood in the pelvis.This is a common cause of chronic pelvic pain in women and causes the appearance of varicose veins in the vulva, vagina, or thigh [34].

Discussion
This systematic review and meta-analysis aimed to report the anatomo-clinical characteristics and prevalence of RV variants and their association with pathologies of the kidney or surrounding structures.The main finding of our review was the correlation between the prevalence of RV variants and different surgeries of the renal region, as well as hemodialysis.
As we observed in this review, variants of RV can be of more than one type, including variants in the origin of RV or journey and entry to the IVC; increased numbers of RV, known as multiple RV, can also occur.Yi et al. (2012) [35] also analyzed RV variants.Only 27 studies were included, in contrast to the present study, which included 90 studies overall and 63 for the meta-analysis of RV journey prevalence.Furthermore, we believe that the prevalence of RV variants is overestimated in their review.They present very high values and define them as common variabilities.Our detailed study shows low prevalence in our different forest plots, suggesting that their data may have been calculated with values from primary studies that only looked for the variant.
The last manuscript associated with the variants of the RV was published in 2019, so this review updates the topic of RV over the past 5 years.In relation to the latter, we make a detailed review of the anatomy of the different variants of the renal vein, adding that we make a clinical correlation, which is why, apart from the years of the last publication on the RV variants, we approached the variant through translational anatomy and providing strong support between the anatomy and the clinical correlations.Hostiuc et al.'s (2019) [103] review does not detail the anatomical characteristics of each RV; in our study, we detailed the variants by subgroup.Their review included 105 studies with an accurate meta-analysis; it differs from our study in that they did not detail the clinical correlations of these.Furthermore, we provided a detailed anatomical description of each variant to provide clinical support for the study of translational anatomy of RV.
There was no indication in the included studies that RV variants had any type of relationship to the sex of the subjects.Similarly, there was no type of indication that RV variants are associated with any specific ethnicity or race; however, to further support this hypothesis, we suggest that more interracial studies should be carried out.With respect to laterality, there was also no type of indication in the studies that variants were associated with the left side or with the right side in specific ethnicities.Finally, age was a value that we did not consider in our study since variants are congenital and thus unrelated to the age of the subjects.
We grouped the variants as RV course variant, multiple RV variant, unusual origin of RV, and variant of RV ramifications.Studies that reported the RV course variant were more commonly found; this is associated with a retroaortic and anteroaortic passage, generating a kind of circumduction on the RV.We did not consider primary studies that showed low prevalences, because if we included all the studies, the results could have been overestimated.We believe that when the prevalence of the variants was high, it is because the sample was intentional and not random; this alters the data from the prevalence meta-analysis, so we decided to not include these results.We generated four prevalence forest plots and found a prevalence of 8% for multiple RV, a prevalence of 5% for course variants, a prevalence of 5% for RV ramifications variants, and a prevalence of 2% for unusual origin of the RV.Finally, we analyzed the publication bias through a funnel plot for each of the prevalence measurements, and we detected a high level of publication bias among some studies, which is why the data must be interpreted with caution.
The heterogeneity of the studies was between 80 and 97%, which is high and could over-or underestimate the reported results.Thus, they should be taken with caution, and we recommend further studies.The AQUA tool was used to assess the bias of the included studies.The results show a low risk of bias in the five domains in all the included studies; therefore the data were included with greater security for the analysis.The case reports presented greater bias in the analysis of results, so we only considered those that presented variants that were underrepresented in the literature or reported some important clinical correlation that supported their inclusion.Finally, while the clinical considerations reported in this study were varied, we focused above all on the intrasurgical care of the abdominal region and the retroperitoneal region, since these variants are often silent and their description or discovery is associated with routine examinations or pathologies of surrounding structures.The only syndrome reported with symptomatology is "nutcracker syndrome", which typically presents signs such as hematuria and must be diagnosed with laboratory tests.This syndrome is very rare in the literature; unfortunately, no article presented a clear prevalence, but we estimate due to the amount of information on the subject that it is less than 1%.
In kidney transplantation, dilemmas can arise due to the positioning of the RV.In the presence of these variants, the veins have acquired an arrangement in the abdominal region, occupying uncommon regions.Patients are often asymptomatic, so many surgeons choose to maintain the arrangements of these variants in transplant surgery [104][105][106].Finally, an equally important clinical correlation is the presence of RV variation before hemodialysis, which is associated with greater complexity in performing the catheterization, because the arrangement of the RV and the surrounding structures may be different.It has also been reported that this could increase the probability of clots or thrombi; a thorough analysis of the region can prevent these complex conditions.

Limitations
This review was limited by the publication and authorship bias of the included studies.First, studies with different results that were in the nonindexed literature in the selected databases may have been excluded.Second, there could be limitations in the sensitivity and specificity of the searches.Finally, the authors personally selected articles.All of this increases the probability of excluding potential cases from countries outside of Asia and North America that are not being reported in the scientific community.

Conclusions
The presence of RV variants has been widely described in the literature.Our results show that the variants of the renal vein can be multiple and that mainly, the lack of knowledge of these could cause iatrogenic injuries during surgeries of structures surrounding the kidney.Regarding patients who receive a kidney transplant and present the RV variant, the surgeon must know how this variant could make work more difficult with these patients; however, prior knowledge could help the surgery to be planned with all these considerations, and these changes could improve the probability of surgical success in these patients.We also believe that more studies that explain how this variant behaves and the symptoms associated with the variant could be necessary.

Figure 2 .
Figure 2. Geographic distribution of studies and subjects included in this review.

Figure 2 .
Figure 2. Geographic distribution of studies and subjects included in this review.

Figure 12 .
Figure 12.Forest plot unusual origin of RV.

Figure 13 .
Figure 13.Funnel plot unusual origin of RV.

Figure 12 .
Figure 12.Forest plot unusual origin of RV.

Figure 12 .
Figure 12.Forest plot unusual origin of RV.

Figure 13 .
Figure 13.Funnel plot unusual origin of RV.

Figure 13 .
Figure 13.Funnel plot unusual origin of RV.

Figure 14 .
Figure 14.Graphic of AQUA checklist for included studies.

Figure 14 .
Figure 14.Graphic of AQUA checklist for included studies.

Table 1 .
Characteristics of included studies.

Table 3 .
Risk of bias of included studies.Risk of bias assessment according to the JBI critical appraisal checklist.

Table 3 .
Risk of bias of included studies.Risk of bias assessment according to the JBI critical appraisal checklist.

Table 4 .
The Joanna Briggs Institute (JBI) critical appraisal checklist for case reports.